Structural basis of tethered agonism and G protein coupling of protease-activated receptors.

ABSTRACT: Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the G_q and G_i heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical recep

SUBMITTER: Guo J 

PROVIDER: S-EPMC11443083 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature